rs78514142

Variant names:

• chr16-49491313-G-A
• rs78514142
• NM_001379286.1:c.3850-9C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001379286.1(ZNF423):​c.3850-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,613,918 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (122 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (128 hom.)
• Consequence: ZNF423 NM_001379286.1 intron
• Scores: Splicing: ADA: 0.9294
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.77
• Publications: 1 publications found

Genes affected

ZNF423 (HGNC:16762): (zinc finger protein 423) The protein encoded by this gene is a nuclear protein that belongs to the family of Kruppel-like C2H2 zinc finger proteins. It functions as a DNA-binding transcription factor by using distinct zinc fingers in different signaling pathways. Thus, it is thought that this gene may have multiple roles in signal transduction during development. Mutations in this gene are associated with nephronophthisis-14 and Joubert syndrome-19. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2012]

ZNF423 Gene-Disease associations (from GenCC):

• nephronophthisis 14

  Inheritance: AD, Unknown, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 16-49491313-G-A is Benign according to our data. Variant chr16-49491313-G-A is described in ClinVar as Benign. ClinVar VariationId is 260537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0778 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379286.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	NM_001379286.1	MANE Select	c.3850-9C>T		intron	N/A	NP_001366215.1
	ZNF423	NM_015069.5		c.3826-9C>T		intron	N/A	NP_055884.2
	ZNF423	NM_001271620.2		c.3646-9C>T		intron	N/A	NP_001258549.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	ENST00000563137.7	TSL:5 MANE Select	c.3850-9C>T		intron	N/A	ENSP00000455588.3
	ZNF423	ENST00000562520.1	TSL:1	c.3646-9C>T		intron	N/A	ENSP00000457664.1
	ZNF423	ENST00000567169.5	TSL:1	c.3475-9C>T		intron	N/A	ENSP00000455061.1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3515 AN: 152130 Hom.: 122 Cov.: 32

Gnomad AFR AF: 0.0801

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00588 AC: 1477 AN: 251302 AF XY: 0.00418

Gnomad AFR exome AF: 0.0803

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00235 AC: 3439 AN: 1461670 Hom.: 128 Cov.: 31 AF XY: 0.00196 AC XY: 1424 AN XY: 727134

African (AFR) AF: 0.0828 AC: 2773 AN: 33476

American (AMR) AF: 0.00432 AC: 193 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0000980 AC: 109 AN: 1111998

Other (OTH) AF: 0.00548 AC: 331 AN: 60392

GnomAD4 genome AF: 0.0231 AC: 3521 AN: 152248 Hom.: 122 Cov.: 32 AF XY: 0.0224 AC XY: 1669 AN XY: 74448

African (AFR) AF: 0.0801 AC: 3325 AN: 41520

American (AMR) AF: 0.00882 AC: 135 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68014

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0131 Hom.: 49

Bravo AF: 0.0261

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Nephronophthisis 14 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.84
PhyloP100		2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78514142; hg19: chr16-49525224;